An important role of skin is to provide protection against infection and physical damage. However, skin also prevents many substances from crossing its epidermal barrier. The skin is not a natural gateway that transdermal delivery systems can exploit; while oral or pulmonary delivery might take place in the gut or lungs, the skin is a physical barrier to overcome.
The skin's ability to inhibit/control the movement of substances across its surface implies that only a small proportion of pharmaceutically active compounds, for example, are suitable for conventional transdermal delivery. Many compounds will be absorbed by the skin; however the absorption typically involves relatively small quantities/concentrations of external molecules per area of skin, per hour, requiring that unpractical large skin contact areas be used to achieve therapeutically effective concentrations of substances via transcutaneous delivery. Furthermore, many compounds do not penetrate the skin at all.
Transcutaneous delivery remains to these days a challenging route of drug administration. A typical challenge faced with inhalable or oral delivery is drug concentration, as it regards the delivery of sufficient quantities of the drug to relatively inaccessible inner surfaces (internal organs) where the delivered compound crosses into the blood. For instance, for systemic delivery, inhalers and formulations for inhalation must incorporate advanced designs to allow deposition into the lungs. Oral technologies must protect the drug from the harsh environment in the stomach for it to reach the epithelium intact. In contrast, while transcutaneous formulations can be applied directly to the surface, the medication is intended to cross the skin. The dense capillary bed close beneath the surface suggests easy access to the systemic circulation; however the compound must cross the skin barrier.
Potential benefits of transcutaneous delivery have spurred several scientists to overcome challenges faced by skin as a barrier by developing active transdermal delivery technologies. These systems use energy to enhance the extent and rate at which pharmaceutical compounds cross the 10 to 20 micrometers dead layer of the skin, the stratum corneum.
Technologies currently under development can be mostly divided into two broad categories. The first category rests on iontophoresis, the ability of an electric current to cause charged particles to move. A pair of adjacent electrodes, placed on the skin, sets up an electrical potential between the skin and the capillaries below. At the positive electrode, positively charged drug molecules are driven away from the skin's surface toward the capillaries. Conversely, negatively charged drug molecules would be forced through the skin at the negative electrode. However, this method requires that the molecules used be charged, which is not automatically the case for all substances of interest. It is also relatively difficult to deliver relatively large molecules using this approach. Finally, this method implies that electrodes and drug formula be set in contact with the skin which can sometimes involve a long contact time for optimized drug delivery, depending on expected rate delivery, if any.
The other category of active transdermal delivery is known as poration. It involves high-frequency pulses of energy, in a variety of forms (radiofrequency (RF) electrical current, lasers, heat, and ultrasound) temporarily applied to the skin to disrupt the stratum corneum, the layer of skin that stops many drug molecules crossing into the bloodstream. Unlike iontophoresis, the energy used in poration technologies is not used to transport the drug across the skin, but to facilitate/allow its movement/penetration. Poration provides a “window” through which drug substances can pass much more readily and rapidly than they would normally. Although this method may be useful to allow some drug molecules to reach dermal capillaries, there is no evidence that it would promote preferential absorption and deposition to specific target structures within the dermis.
For example, the Israeli company, TransPharma Medical, is using alternating current at radio frequencies to create aquatic throughways, about 100 micrometers wide, across the stratum corneum. The number of active electrodes determines the number of pores and thus, amongst other factors, the rate at which drug will cross the skin. Importantly, newly created channels only reach as far as the epidermis, where there are no nerves or blood vessels. The main limitation of this technology is the depth of penetration of these channels within the epidermis so that not enough drug molecules are able to get to targeted structures in the dermis to achieve a significant clinical improvement.
Laser Light
Norwood Abbey's Laser Assisted Delivery® (LAD) technology comprises an electronic, handheld Er:YAG laser device, which is pressed against the skin exposing the treatment area to a burst of low level laser light. Although this process disrupts the barrier function of the skin long enough to allow drug molecules to move through more quickly, the physiological effects triggered by the laser are relatively mild, involving rearrangement of lipids and proteins or removal of dead cells. This method, which can involve skin contact, has therefore the potential of allowing only limited movements across the epidermal layer.
U.S. Pat. No. 5,814,008, issued Sep. 29, 1998 to Chen et al., discloses a method of photodynamic therapy (PDT) wherein the treated tissue may be heated before the application of a photosensitizer, to facilitate its perfusion into the tissue and enhance efficacy of the subsequent light therapy. The heating may be achieved by a number of means, preferably by irradiating the tissue with a light having a wavelength substantially different than the wavelength of light used for the PDT treatment. However, the PDT treatment disclosed in this document is invasive in nature and no transcutaneaous delivery of the photosensitizer is therefore contemplated as the radiation is applied through a probe inserted within the tissues to be treated.
Heat
To ablate the stratum corneum, bursts of electric current cause points of filaments in contact with the skin to heat up for a few milliseconds at a time. Behind these filaments is the drug reservoir, for example a patch, from which the formulation diffuses past the filament and through the skin. The need for repeated microtrauma to the skin, the requirement of sometimes large contact areas to achieve proper drug concentration and the need for a patch with prolonged contact time are all disadvantages of this method. Also, almost perfect contact of the heating apparatus (pad, etc.) must be ensured during the procedure to provide a uniform preparation of the targeted area.
Sound
The final energy form, sound (or more specifically, ultrasound) is also being used for transdermal delivery. Sound technology, known as SonoPreparation®, uses a 15-second burst of ultrasound at 55 kHz. Sound waves create cavitations bubbles in the tissue, disrupting the lipid bilayers of stratum corneum cells, which results in the creation of microchannels. The SonoPreparation device consists of a handpiece, linked by a wire to a base unit, pressing an ultrasonic horn onto the skin treatment area. The limitations of this method are the same as for the ones described previously for heat.
In view of the above, there is a need to provide novel methods for the treatment of skin tissues.